salicylates and Pulmonary-Fibrosis

Topics: Aging; Alveolar Epithelial Cells; Animals; Apoptosis; Asbestos; Catalase; Cell Line; DNA Damage; DNA, Mitochondrial; Female; Gene Expression Regulation; Glucuronidase; Klotho Proteins; Male; Mice; Mitochondria; Organometallic Compounds; Oxidants; Oxidative Stress; Protective Agents; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Receptor, IGF Type 1; Receptors, Fibroblast Growth Factor; RNA, Messenger; Salicylates; Signal Transduction

Alveolar epithelial cell (AEC) injury and mitochondrial dysfunction are important in the development of lung fibrosis. Our group has shown that in the asbestos exposed lung, the generation of mitochondrial reactive oxygen species (ROS) in AEC mediate mitochondrial DNA (mtDNA) damage and apoptosis which are necessary for lung fibrosis. These data suggest that mitochondrial-targeted antioxidants should ameliorate asbestos-induced lung.. To determine whether transgenic mice that express mitochondrial-targeted catalase (MCAT) have reduced lung fibrosis following exposure to asbestos or bleomycin and, if so, whether this occurs in association with reduced AEC mtDNA damage and apoptosis.. Compared to WT, crocidolite-exposed MCAT mice exhibit reduced pulmonary fibrosis as measured by lung collagen levels and lung fibrosis score. The protective effects in MCAT mice were accompanied by reduced AEC mtDNA damage and apoptosis. Similar findings were noted following bleomycin exposure. Euk-134, a mitochondrial SOD/catalase mimetic, attenuated MLE-12 cell DNA damage and apoptosis. Finally, compared to WT, asbestos-induced MCAT AT2 cell ROS production was reduced.. Our finding that MCAT mice have reduced pulmonary fibrosis, AEC mtDNA damage and apoptosis following exposure to asbestos or bleomycin suggests an important role for AEC mitochondrial H

Topics: Administration, Inhalation; Animals; Asbestos; Bleomycin; Caspase 3; Catalase; Collagen; DNA, Mitochondrial; Epithelial Cells; Gene Expression; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Intubation, Intratracheal; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Proteins; Organometallic Compounds; Peptides; Pulmonary Alveoli; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein C; Reactive Oxygen Species; Salicylates; Transgenes

A mouse model of hypersensitivity pneumonitis was generated by challenge with a thermophilic actinomycete. Oxygen radical scavengers were administered to challenged mice: vitamin E at 1000 units daily, polyethylene glycol-superoxide dismutase (SOD) at 500 units daily, polyethylene glycol-catalase at 10,000 units daily, 1,3,dimethyl-2-thiourea (DMTU) at 2 mg daily, and the biomimetic SOD, copper(II) [diisopropyl salicylate]2 (CuDIPS) at 1 mg daily. At three weeks after actinomycete challenge, a 10-fold increase in bronchoalveolar (BAL) cell number was observed. Treatments with catalase or DMTU were without effect on the BAL cell number in challenged mice. However, infusion of vitamin E was associated with an increased BAL cell influx (15-fold increase at two and three weeks). Similarly, treatment with PEG-SOD and CuDIPS resulted in an increase in cell number at two and three weeks. PEG-SOD or CuDIPS treatment resulted in a strong neutrophilia, whereas control challenged mice had a cellular influx mostly of macrophages and lymphocytes. Vitamin E treatment of challenged mice led to an increased T lymphocyte recruitment at two and three weeks. In vitro studies showed that actinomycete challenge was associated with an enhancement of alveolar macrophage O2- release, which was blocked by PEG-SOD, vitamin E, or DSC treatment but was unaffected by catalase or DMTU treatment. In control challenged mice, there was a 25-fold increase in the BAL albumin concentration at two weeks. PEG-SOD, vitamin E, or CuDIPS treatment all decreased the albumin concentration; the three modulators also diminished lung fibrosis at two or three weeks, as seen by a decrease in lung hydroxyproline and collagen synthesis by lung fibroblasts. Examination of sections from lungs of challenged animals showed evidence of cellular infiltrates around the bronchi and the blood vessels. Challenged mice given continuous infusions of vitamin E, SOD, or CuDIPS had lung histological scores that were significantly lower than control challenged mice or challenged mice treated with catalase or DMTU. Thus, therapies based on O2- scavenging or treatment with a general antioxidant such as vitamin E may hold some promise in the treatment of hypersensitivity pneumonitis.

Topics: Animals; Antigens, Fungal; Antioxidants; Bronchoalveolar Lavage Fluid; Collagen; Farmer's Lung; Fibroblasts; Free Radical Scavengers; Hydroxyproline; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; Micromonosporaceae; Neutrophils; Pulmonary Fibrosis; Reactive Oxygen Species; Salicylates; Specific Pathogen-Free Organisms; Superoxide Dismutase; T-Lymphocytes; Thiourea; Vitamin E

The hydroxyl radical (.OH) is a highly reactive oxygen free radical that has been implicated as a cause of lung injury following exposure to silica and silicates. Despite evidence that silica generates .OH in vitro, there has been no previous demonstration of in vivo production of .OH after exposure to nonfibrous mineral oxide dusts. We tested the hypothesis that instillation of silica into rat lungs is associated with greater .OH production and acute lung inflammation in vivo relative to the instillation of a less toxic nonsilicate particle, titanium dioxide. The production of .OH in the lungs following dust instillation was measured using sodium salicylate as an .OH trap. Seven days after dust exposure, the rats were given intraperitoneal salicylate, the lungs isolated, and salicylate hydroxylation products (2,3- and 2,5-dihydroxybenzoic acid), reflecting .OH, were measured. There was significantly more 2,3-dihydroxybenzoic acid in silica-exposed lungs compared with lungs instilled with titanium dioxide. In addition, the instillation of silica into rat lungs in vivo was associated with a greater acute inflammatory response. We conclude that following in vivo exposure, silica stimulates greater .OH production relative to the less toxic particle, titanium dioxide. These differences in .OH generation correspond to disparities in acute lung inflammation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Dust; Gentisates; Hydroxybenzoates; Hydroxyl Radical; Hydroxylation; Lung; Lung Injury; Organ Size; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Salicylates; Salicylic Acid; Silicon Dioxide; Silicosis; Titanium